Corneal infections caused by the Gram positive bacterial Staphylococcus aureus (Staph) and Streptococcus pneumoniae (Strep) occur in the USA and worldwide, causing painful, sight-threatening disease. Further, methicillin resistant S. aureus (MRSA) are becoming more common, as MRSA are more difficult to treat and are more virulent than methicillin sensitive strains. The Aims of this proposal will focus on the role of IL-1 in S. aureus and S. pneumoniae keratitis because our preliminary data show that this cytokine has a critical role in regulating corneal infection by either bacteria. IL-1 secretion requires two signals - Signal 1 for transcription, and Signal 2 for enzymatic processing; therefore, Aim 1 will examine the role of bacterial cell wall in inducing NOD2/RIP2 signaling in IL-1-/- transcription, and Aim 2 will examine the role of Staph aureus -hemolysin and Strep pneumoniae pneumolysin induction of the NLRP3/ASC inflammasome in caspase-1 mediated IL-1 cleavage. Aim 3 will examine the role of ATP and purinergic receptors in amplifying inflammasome activity and IL-1 production. Results of these studies will identify novel pathways that can be targeted for anti-inflammatory therapies.